{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:58:44Z","timestamp":1790780324749,"version":"4.1.0"},"posted":{"date-parts":[[2025,10,26]]},"group-title":"Immunology","reference-count":27,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T00:00:00Z","timestamp":1761436800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 AI143741 and R21 AI151522"],"award-info":[{"award-number":["R01 AI143741 and R21 AI151522"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                  asymptomatically colonizes the human nasopharynx, where epithelial tolerance maintains mucosal homeostasis. However, influenza A virus (IAV) co-infection transforms this tolerogenic state into an inflammatory environment that promotes bacterial outgrowth and invasion. Here, we identify a TGF-\u03b21 dependent epithelial program that sustains mucosal tolerance during\n                  <jats:italic>Spn<\/jats:italic>\n                  colonization and demonstrate that IAV co-infection disrupts this pathway through IL-17RA-NF-\u03baB driven inflammation in the nasopharynx. In a murine colonization model, TGF-\u03b21 blockade enhanced pro-inflammatory cytokine production and neutrophil recruitment, resulting in inflammation-driven\n                  <jats:italic>Spn<\/jats:italic>\n                  clearance. IAV co-infection suppressed epithelial TGF-\u03b21 signaling, increased TRAF6\/NF-\u03baB activation, and impaired tight junction integrity, leading to\n                  <jats:italic>Spn<\/jats:italic>\n                  dissemination. Mechanistically, IL-17RA signaling contributed to the hyperactivation of the TRAF6\/NF-\u03baB axis. Pharmacologic inhibition of TRAF6 or NF-\u03baB restored epithelial barrier function and reduced\n                  <jats:italic>Spn<\/jats:italic>\n                  translocation in a human air-liquid interface nasopharyngeal epithelial model. These findings reveal a conserved epithelial signaling axis through which influenza disrupts mucosal tolerance and promotes\n                  <jats:italic>Spn<\/jats:italic>\n                  invasion, highlighting the canonical TRAF6-NF-\u03baB pathway as a potential therapeutic target to preserve epithelial integrity and mitigate\n                  <jats:italic>Spn<\/jats:italic>\n                  infection during viral-bacterial co-infection of the upper respiratory tract.\n                <\/jats:p>","DOI":"10.1101\/2025.10.25.684585","type":"posted-content","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T04:30:13Z","timestamp":1761539413000},"source":"Crossref","is-referenced-by-count":2,"title":["NF-\u03baB driven inflammation mediates loss of upper airway epithelial tolerance to\n                  <i>Streptococcus pneumoniae<\/i>\n                  during influenza co-infection"],"prefix":"10.64898","author":[{"given":"Zahrasadat","family":"Navaeiseddighi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed","family":"Hasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Schmit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamanah","family":"Ahsan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramkumar","family":"Mathur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junguk","family":"Hur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadeem","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025102818250991000_2025.10.25.684585v1.1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2025.1566502"},{"key":"2025102818250991000_2025.10.25.684585v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofad192"},{"key":"2025102818250991000_2025.10.25.684585v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(04)00938-7"},{"key":"2025102818250991000_2025.10.25.684585v1.4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02275"},{"key":"2025102818250991000_2025.10.25.684585v1.5","doi-asserted-by":"publisher","DOI":"10.1093\/jpids\/piad004"},{"key":"2025102818250991000_2025.10.25.684585v1.6","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.GPP3-0004-2018"},{"key":"2025102818250991000_2025.10.25.684585v1.7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00358"},{"key":"2025102818250991000_2025.10.25.684585v1.8","doi-asserted-by":"publisher","DOI":"10.4161\/21645515.2014.979631"},{"key":"2025102818250991000_2025.10.25.684585v1.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501254102"},{"key":"2025102818250991000_2025.10.25.684585v1.10","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-009-0557-x"},{"key":"2025102818250991000_2025.10.25.684585v1.11","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.643326"},{"key":"2025102818250991000_2025.10.25.684585v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdsr.2023.12.006"},{"key":"2025102818250991000_2025.10.25.684585v1.13","doi-asserted-by":"publisher","DOI":"10.1128\/msphere.00984-21"},{"key":"2025102818250991000_2025.10.25.684585v1.14","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a001651"},{"key":"2025102818250991000_2025.10.25.684585v1.15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011847"},{"key":"2025102818250991000_2025.10.25.684585v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiz193"},{"key":"2025102818250991000_2025.10.25.684585v1.17","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-3537"},{"key":"2025102818250991000_2025.10.25.684585v1.18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002649"},{"key":"2025102818250991000_2025.10.25.684585v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-01911005-2"},{"key":"2025102818250991000_2025.10.25.684585v1.20","doi-asserted-by":"publisher","DOI":"10.1080\/21688370.2021.1883965"},{"key":"2025102818250991000_2025.10.25.684585v1.21","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms12122526"},{"key":"2025102818250991000_2025.10.25.684585v1.22","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2024.1346087PMIDs:38736751"},{"key":"2025102818250991000_2025.10.25.684585v1.23","doi-asserted-by":"publisher","DOI":"10.4161\/21688370.2014.982424"},{"key":"2025102818250991000_2025.10.25.684585v1.24","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adj1120"},{"key":"2025102818250991000_2025.10.25.684585v1.25","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00530-16"},{"key":"2025102818250991000_2025.10.25.684585v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110456"},{"key":"2025102818250991000_2025.10.25.684585v1.27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.927955"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.25.684585","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:53:35Z","timestamp":1768470815000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.25.684585"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,26]]},"references-count":27,"URL":"https:\/\/doi.org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